Transparent transdermal nicotine delivery devices

ABSTRACT

A transparent transdermal delivery device for delivering nicotine which has an Opacity Index of less than 48.6%.

CLAIM OF PRIORITY

This application is a continuation of U.S. application Ser. No.11/841,789, filed Aug. 20, 2007, which is a continuation of U.S.application Ser. No. 10/871,458, filed Jun. 18, 2004, which is acontinuation of U.S. application Ser. No. 09/464,305, filed Dec. 15,1999, which claims the benefit of U.S. provisional patent ApplicationsNos. 60/112,730, filed Dec. 18, 1998; 60/124,679, filed Mar. 16, 1999;and 60/126,798, filed Mar. 30, 1999, all of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to transdermal delivery devices foradministering nicotine for use in smoking cessation treatments. Inparticular, the invention is directed to transdermal nicotine deliverydevices which are transparent.

BACKGROUND OF THE INVENTION

The transdermal route of parenteral drug delivery provides manyadvantages over other administration routes. Transdermal systems fordelivering a wide variety of drugs or other beneficial agents aredescribed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494;4,031,894; 4,144,317; 4,201,211; 4,286,592; 4,314,557; 4,379,454;4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502;4,698,062; 4,704,282; 4,725,272; 4,781,924; 4,788,062; 4,816,258;4,849,226; 4,904,475; 4,908,027; 4,917,895; 4,938,759; 4,943,435;5,004,610; 5,071,656; 5,122,382; 5,141,750; 5,284,660; 5,314,694;5,342,623; 5,411,740; and 5,635,203, which are hereby incorporated intheir entirety by reference.

The administration of nicotine buccally, nasally and transdermally toassist a patient desiring to quit smoking has been shown to beclinically effective in reducing the rate of recidivism. Nicotinechewing gum and transdermal nicotine are two of the most widely usedforms of nicotine replacement therapy currently available. Transdermaldevices for administering nicotine are disclosed in U.S. Pat. Nos.4,597,961; 4,758,434; 4,764,382; 4,839,174; 4,908,213; 4,915,950;4,943,435; 4,946,853; 5,004,610; 5,016,652; 5,077,104; 5,230,896;5,411,739; 5,462,745; 5,508,038; 5,599,554; 5,603,947 and 5,726,190, forexample, which are hereby incorporated in their entirety by reference.

Most of the transdermal drug delivery devices of the prior art utilizean impermeable backing on the skin distal surface of the device toprotect the device from damage and to prevent loss of the activeingredient(s). In order to improve user satisfaction, these backinglayers are often tinted to a color similar to skin tones. However, ascan be readily appreciated, it is not commercially practical to providepigmented backing layers for transdermal systems which approximate allskin colors.

Another approach that has been taken is to provide transparenttransdermal systems in which all elements forming a device aresufficiently transparent to permit the natural skin color to be visiblethrough the device. Marketed products which take this approach includethe ALORA® and CLIMARA® estrogen replacement patches and the DURAGESIC®transdermal fentanyl delivery system. When these devices are applied tothe skin, the patient's natural skin color is visible through the patch,making the presence of the patch extremely inconspicuous. Governmentregulations require that these products bear identifying indicia, butthe indicia can be printed on these devices in light colored or whiteink which is not noticeable from a distance of several feet, but isstill readable on close inspection.

Such transparent patches have been found useful with non-volatile drugssuch as fentanyl and hormone replacement steroids, but no suchtransparent product has been developed for the delivery of nicotine.

Nicotine is a liquid alkaloid that is colorless, volatile, stronglyalkaline, readily oxidized, subject to degradation on exposure to lightand highly permeable through not only the human skin, but also many ofthe polymers conventionally used in the fabrication of backing layersand packaging materials for transdermal products (see for example U.S.Pat. No. 5,077,104). As a result, the backing layers of the transdermalnicotine delivery devices currently available utilize opaque,skin-colored multilaminate films which typically contain a metalizedlayer, such as aluminum.

Not only do the commercially available transdermal nicotine patches useopaque backings, but many of these devices, due to the complexities ofhandling and processing nicotine, have other components which are nottransparent. For example, the original Prostep® transdermal nicotineproduct used a drug reservoir in the form of an opaque white gel, heldin place by an opaque adhesive overlay. The HABITROL® and NICOTROL®nicotine patches incorporated absorbent pads in the drug reservoir inwhich the nicotine was absorbed.

It has also been proposed to co-administer nicotine with othersubstances that improve nicotine cessation therapy. See, for example,U.S. Pat. Nos. 4,908,213; 5,599,554; and 5,726,190 noted above; and WO97/33581.

SUMMARY OF THE INVENTION

The present invention relates to transparent transdermal deliverydevices for the transdermal administration of nicotine, either alone orin combination with other agents.

Such devices should be sufficiently transparent so that the subject'sskin can be clearly visible through the device when it is placed on theskin. Identifying indicia can be printed on the device in light coloredor white ink in a manner which is not noticeable from a short distance,but is readable on close inspection.

DETAILED DESCRIPTION OF THE INVENTION

Preferred devices of this invention utilize, as the backing layer, atransparent polymeric film which has a permeability to nicotine of lessthan 1 μg/cm²/hr, preferably less than 0.5 μg/cm²/hr, a solubility fornicotine that is less than 1% by weight and preferably less than 0.1%.Such films are preferably less than about 6 mils thick and mostpreferably about 2-4 mils thick. Such films are used in combination withone or more of the conventional elements of a transdermal device (otherthan the removable release liner) such as the drug reservoir, adhesiveand rate controlling membranes, which must also be sufficientlytransparent as to permit the natural skin color to be clearly visiblethrough the assembled device after placement on the skin. The finishedproduct should have an Opacity Index of less than about 48.6%,preferably less than about 35.11% and more preferably less than 20%.

In addition to being transparent and being sufficiently impermeable tonicotine, the backing layer must also have sufficient mechanicalstrength and physical integrity to maintain the system intact throughoutits intended administration period, which is typically 18-24 hours, andmust provide a stable interface with adjoining layers such as the drugreservoir or adhesive layers of the transdermal device. This combinationof properties is not always found in one material, and thus thetransparent backing layers used on the devices of this invention can bemultilaminate films. In addition to having a low permeability tonicotine, a backing layer must also have a low solubility for nicotine.This is because nicotine is toxic and it could be dangerous for a child,for example, to lick the backing layer if it contained a substantialamount of dissolved nicotine.

Suitable polymer materials possessing properties required by thisinvention include SCOTCHPAK® 1220 film, which is a polyethyleneterephthalate/ethylene vinyl acetate (PET EVA), bilaminate film sold bythe 3M Company, Minneapolis, Minn., and SARANEX® 2057 film, which is ahigh density polyethylene (HDPE)/ethylene acrylic acid (EAA)/nylon/EAAmultilaminate available from the Dow Chemical Company, Midland, Mich.Nitrile rubber graft copolymers with acrylonitrile and methyl acrylatesold as Barex® films described in U.S. Pat. No. 5,077,104 noted above,can also be used.

These films, comprising a graft copolymer formed from about 73-77%acrylonitrile and from about 23-27% methyl acrylate copolymerized in thepresence of about 8-10 parts by weight of butadiene/acrylonitrilecopolymers containing approximately 70% by weight of polymer unitsderived from butadiene are preferred backing materials.

The transparent transdermal delivery devices of this invention can be ofany of the forms described in the aforementioned patents. The preferredform, however, comprises a laminate of the backing layer, a nicotinereservoir layer which contains nicotine dissolved in a carrier at aconcentration below the saturation concentration of nicotine in thecarrier. If the drug reservoir component is self adhesive, a simplemonolithic device could be employed. However, in many cases it isdesirable to include additional components such as rate controllingmembranes, and a separate adhesive layer for maintaining the devices onthe skin such as is described in U.S. Pat. Nos. 5,004,610 and 5,342,623listed above. It is further contemplated that in addition to nicotine,the device may also contain other drugs or other active substances whichcooperate with or enhance the effect of nicotine in smoking cessation,smoking replacement or smoking substitution therapy. For all thesedevices, a removable release liner would normally be applied on theadhesive surface of the patch that is used to keep the device on theskin, which release liner is removed prior to use.

Various materials suited for fabrication of the various components areknown in the art and are disclosed in the aforementioned patents.

The adhesive component is preferably a pressure sensitive adhesiveincluding, but not limited to, polysiloxanes, polyacrylates,polyurethanes, acrylic adhesives including cross linked or uncrosslinked acrylic copolymers, vinyl acetate adhesives, ethylenevinylacetate copolymers, and natural or synthetic rubbers includingpolybutadienes, polyisoprenes, and polyisobutylene adhesives, andmixtures and graft copolymers thereof. The devices may also be providedwith hydrophilic water absorbing polymers known in the art such aspolyvinyl alcohol and polyvinyl pyrolidone individually or incombination. The adhesive can be used to form a monolithic deliverydevice in which the nicotine is dissolved in the adhesive to form aself-adhesive drug reservoir. Alternatively, the adhesive can be appliedto the surface of a non-adhesive reservoir in which nicotine isdissolved, to form a multilaminate device. A rate-controlled membranecan also be interfaced between the nicotine reservoir and the adhesive,as is known to the art.

The nicotine can be administered in combination with another agent whichcould include anti-anxiolytics, antihypertensives, antidepressants, andappetite suppressants, such as fluoxetine, caffeine, buspirone,phenylpropanolamine, clonidine, paroxetine, citalopram, and sertraline.

The nicotine in the device is present in the reservoir at a subsaturatedcondition (i.e. less than unit activity) such that no undissolvednicotine is present in the reservoir. If other agents are present in thedevice, they are preferably present fully dissolved, but can be presentin undissolved form so long as the end product displays the properdegree of transparency.

In the present invention, nicotine and optionally other agents to beco-administered are delivered through the skin or other body surface ata therapeutically effective rate for a predetermined time period whichfor nicotine is preferably 16-24 hours.

The transdermal therapeutic devices of the present invention areprepared in a manner known in the art, such as by those proceduresdescribed in the transdermal device patents listed previously herein.

The following example is offered to illustrate the practice of thepresent invention and is not intended to limit the invention in anymanner.

Example 1

Various commercially available transdermal patches were tested todetermine their transparency and compared to the transparent nicotinepatches according to this invention. The nicotine patches were preparedas set forth in Example IV of U.S. Pat. No. 5,004,610 with a PET/EVA(SCOTCHPAK® 1220 film, 3M, Minneapolis, Minn.) or SARANEX® film (DowChemical Company, Midland, Mich.) backing substituted for the SCOTCHPAK1006 film backing. The light transmitted through the various systems wasmeasured by a MACBETH 1500/Plus color measurement system (KollmorgemInstruments Corp., Newburgh, N.Y.). Table 1 shows the Opacity Index,which is the percentage of incidental light which is absorbed by passagethrough the device, for the various systems tested.

TABLE 1 Patch Opacity Patch Opacity Index MINITRAN ®  48.6% ALORA ®20.21% FEMPATCH ® 35.11% CLIMARA ® 19.33% Ex. 1 - Nicotine withSARANEX ® backing 17.04% Ex. 1 - Nicotine with PET/EVA backing 19.66%

The MINITRAN® nitroglycerine system is clearly visible from a distanceof about 5 feet, whereas the FEMPATCH® patch is significantly lessnoticeable. The ALORA®, CLIMARA® and NICODERM® patches, however, areextremely inconspicuous. Accordingly, transdermal devices according tothis invention should have an Opacity Index less than 48.6%, preferablyless than 35.11%, more preferably less than 20%.

Having thus generally described our invention and preferred embodimentsthereof, it is apparent that various modifications and substitutionswill be apparent to workers skilled in the art. These modifications andsubstitutions can be made without departing from the scope of ourinvention which is limited only by the following claims.

1-9. (canceled)
 10. A method for transdermal administration of nicotine,the method comprising: applying a transdermal nicotine delivery deviceto a skin surface, the device comprising: a backing layer comprising amaterial selected from the group consisting of PET/EVA laminates,HDPE/EAA/nylon/EAA multilaminate, and a film comprising a graftcopolymer formed from about 73-77% acrylonitrile and from about 23-27%methyl acrylate copolymerized in the presence of about 8-10 parts byweight of butadiene/acrylonitrile copolymers; and a drug reservoir layercomprising nicotine, wherein the device is sufficiently transparent topermit the skin surface to be visible through the device.
 11. The methodof claim 10, wherein the drug reservoir layer further comprises aself-adhesive drug reservoir.
 12. The method of claim 10, wherein thedrug reservoir layer further comprises one or more adhesives.
 13. Themethod of claim 12, wherein the one or more adhesives comprises one ormore pressure sensitive adhesives selected from the group consisting ofpolysiloxanes, polyacrylates, polyurethanes, acrylic adhesives, vinylacetate adhesives, ethylene vinyl acetate copolymers, natural orsynthetic rubbers, and mixtures and graft copolymers thereof.
 14. Themethod of claim 10, wherein the device is provided with one or morehydrophilic water absorbing polymers.
 15. The method of claim 10,wherein the backing layer has a nicotine permeability of less than 1.0μg/cm²/hr.
 16. The method of claim 10, wherein the backing layer has anicotine permeability of less than 0.5 μg/cm²/hr.
 17. The method ofclaim 10, wherein the backing layer has a solubility for nicotine ofless than 1 wt %.
 18. The method of claim 10, wherein the backing layerhas a solubility for nicotine of less than 0.1 wt %.
 19. The method ofclaim 10, wherein the device has an Opacity Index of less than 48.6%.20. The method of claim 10, wherein the device has an Opacity Index ofless than 35.11%.
 21. The method of claim 10, wherein the device has anOpacity Index of less than 20%.
 22. The method of claim 10, wherein thebacking layer comprises a PET/EVA laminate.
 23. The method of claim 10,wherein the backing layer comprises a HDPE/EAA/nylon/EAA multilaminate.24. The method of claim 10, wherein the backing layer comprises a filmcomprising a graft copolymer formed from about 73-77% acrylonitrile andfrom about 23-27% methyl acrylate copolymerized in the presence of about8-10 parts by weight of butadiene/acrylonitrile copolymers containingapproximately 70% by weight of polymer units derived from butadiene. 25.The method of claim 10, wherein the device provides delivery of nicotinefor a period of 18-24 hours.
 26. The method of claim 10, wherein thedevice further comprises an adhesive for maintaining the device on theskin surface.
 27. A method for transdermal administration of nicotine,the method comprising: administering a transdermal nicotine deliverydevice to a skin surface, the device comprising: a backing layercomprising a material selected from the group consisting of PET/EVAlaminates, HDPE/EAA/nylon/EAA multilaminate, and a film comprising agraft copolymer formed from about 73-77% acrylonitrile and from about23-27% methyl acrylate copolymerized in the presence of about 8-10 partsby weight of butadiene/acrylonitrile copolymers; and a drug reservoirlayer comprising nicotine, wherein the device has an Opacity Index ofless than 48.6%.
 28. A method for transdermal administration ofnicotine, the method comprising: obtaining a transdermal nicotinedelivery device, the device comprising: a backing layer comprising amaterial selected from the group consisting of PET/EVA laminates,HDPE/EAA/nylon/EAA multilaminate, and a film comprising a graftcopolymer formed from about 73-77% acrylonitrile and from about 23-27%methyl acrylate copolymerized in the presence of about 8-10 parts byweight of butadiene/acrylonitrile copolymers; and a drug reservoir layercomprising nicotine, wherein the device is sufficiently transparent topermit the skin of a subject to which it is applied to be visiblethrough the device, and applying the device to the skin of a subject.29. The method of claim 28, wherein the device has an Opacity Index ofless than 48.6%.